Pharmaceutical compositions comprising meloxicam

ABSTRACT

Disclosed herein are compositions comprising an NSAID such as meloxicam in combination with a cyclodextrin and/or a carbonate or a bicarbonate. These compositions may be orally administered, for example, to improve the bioavailability or pharmacokinetics of the NSAID for the treatment of conditions such as pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/902,770, filed Feb. 22, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/797,955, filed Oct. 30, 2017; which is acontinuation-in-part of U.S. patent application Ser. No. 15/132,130,filed Apr. 18, 2016, now U.S. Pat. No. 9,821,075; which is acontinuation of International Pat. App. No. PCT/US2016/026991, filedApr. 11, 2016, which claims the benefit of U.S. Provisional Pat. App.Nos. 62/114,215, filed Feb. 10, 2015, and 62/259,993, filed Nov. 25,2015; the above U.S. patent application Ser. No. 15/797,955 also claimsthe benefit of U.S. Provisional Pat. App. Nos. 62/526,884, filed Jun.29, 2017, and 62/536,466, filed Jul. 25, 2017; all of the abovedocuments are hereby incorporated by reference in their entireties.

BACKGROUND

Meloxicam, which has the structure:

is a nonsteroidal anti-inflammatory (NSAID) drug that exhibitsanti-inflammatory, analgesic, and antipyretic activities. The meloxicammechanism of action may be related to prostaglandin synthetase(cyclo-oxygenase, COX) inhibition which is involved in the initial stepsof the arachidonic acid cascade, resulting in the reduced formation ofprostaglandins, thromboxanes and prostacylin.

SUMMARY

Meloxicam and some other NSAIDs have poor aqueous solubility which mayreduce bioavailability and slow the onset of pain relief resulting fromtheir use. One means of increasing the solubility and bioavailability ofmeloxicam is through the use of cyclodextrins. Cyclodextrin (also knownas cycloamyloses) are generally cyclic polysaccharides which form abucket-like shape. Cyclodextrins help to increase bioavailability ofother molecules because cyclodextrins are hydrophobic on the inside andhydrophilic on the inside which helps to facilitate the transport ofmolecules. The naturally occurring cyclodextrins include six, seven, andeight glucose units (α, β, and γ-cyclodextrin, respectively). However,synthetic cyclodextrins containing more or less glucose units arepossible. In aqueous solutions, cyclodextrins can form complexes (i.e.,an inclusion complex) with drugs by incorporating the drug into thecenter/hydrophobic portion of the cyclodextrin ring; althoughcyclodextrin compounds are also known to aggregate around a drug in amicelle-type structure. This ability of cyclodextrins may allow them toact as carriers to increase the bioavailability of less soluble drugs.

Some embodiments include an inclusion complex of meloxicam in acyclodextrin.

Some embodiments include a dosage form comprising: 1) an inclusioncomplex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonateor a bicarbonate.

Some embodiments include a method of administering meloxicam orally,comprising orally administering a dosage form described herein to apatient in need of treatment.

Some embodiments include a method of administering meloxicamintravenously, comprising intravenously administering a dosage formdescribed herein to a patient in need of treatment.

Disclosed herein are formulations for an inclusion complex ofcyclodextrin and meloxicam with bicarbonate and methods of use thereof.

Disclosed herein are formulations and methods for delivering meloxicamwith cyclodextrin to a subject by oral, enteral, intravenous,intramuscular, subcutaneous, intranasal, or other parenteral means.

Disclosed also are methods for treating pain and pain associated withconditions by delivering a dosage form with meloxicam, cyclodextrin, andbicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous,intranasal, or other parenteral means to a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a depiction of the results described in Example 2 andcontained in Table 6.

FIG. 2 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 3 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 4 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 5 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 6 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 7 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 8 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 9 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 10 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 11 is a plot of meloxicam plasma concentration at various timepoints over the first 24 hours for an embodiment of a dosage formdescribed herein and a commercially available meloxicam dosage form.

DETAILED DESCRIPTION

Provided herein are dosage forms with NSAIDs (such as meloxicam) andcyclodextrin (optionally in an inclusion complex), and/or bicarbonate,and methods of treatment using the dosage form.

A dosage form may be given enterally including, but not limited to,oral, sublingual, or rectal delivery, or parenterally including, but notlimited to, intravenous, intramuscular, intranasal, or subcutaneousdelivery.

Some methods include administration of a product that combines an NSAIDthat is formulated with: a) a cyclodextrin and/or b) a buffering agent.In some embodiments, the method involves treating a patient with apharmaceutical formulation comprising meloxicam and a cyclodextrinand/or a carbonate/bicarbonate. Method embodiments may also includetreating a patient to increase the bioavailability of meloxicam in thepatient or increase the rate at which the meloxicam becomesbioavailable.

The term “treating” or “treatment” broadly includes any kind oftreatment activity, including the diagnosis, cure, mitigation, orprevention of disease in man or other animals, or any activity thatotherwise affects the structure or any function of the body of man orother animals.

The dosage form may be used to treat, or provide relief of, any type ofpain including, but not limited to, migraine and other types ofheadache, inflammatory pain, musculoskeletal pain, neuropathic pain,chronic pain, acute pain, localized pain, systemic pain, cancer-relatedpain, acute pain, pain due to injury, pain due to illness (e.g., fever),post-operative pain, etc. In some instances, pain relief may bepalliative, or pain relief may be provided independent of improvement ofthe disease or condition or the underlying cause of the disease orcondition. For example, although the underlying disease may not improve,or may continue to progress, an individual suffering from the diseasemay experience pain relief. In some embodiments, the pain affects amuscle, nerve, cartilage, bone, ligament, tendon, tendon sheaths,bursae, or joint.

In some embodiments, the dosage form may also be administered to relievearthritis pain. In some embodiments the dosage form may be administeredto relieve other signs and/or symptoms of arthritis. Examples ofarthritis include, but are not limited to, rheumatoid arthritis,juvenile rheumatoid arthritis (pauciarticular and polyarticular course),osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid),arthropathies, non-articular rheumatism, peri-articular disorders, axialspondyloarthritis, transient osteoarthritis of the hip, vertebral crushfractures, osteoporosis, and neuropathic arthropathies includingCharcot's foot, axial spondyloarthritis including ankylosingspondylitis, and SAPHO syndrome. In other embodiments, the arthritispain may be chronic or acute. In some embodiments the dosage form may beadministered to relief the signs and/or symptoms of an arthritisincluding but not limited osteoarthritis

For some methods, administration of the dosage form may achieve areduction in pain that lasts at least about one hour, two hours, threehours, four hours, six hours, at least about eight hours, about eight toabout 24 hours, or about 24 hours. In other embodiments, administrationof the dosage form may achieve a reduction in pain that is observed atabout 10 minutes, at about 30 minutes, at about one hour, at about twohours, at about three hours, at about four hours, at about five hours,at about six hours, at less than 15 minutes, at less than 20 minutes, 30minutes, at less than one hour, at less than two hours, at less thanthree hours, at about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60minutes, or other time period bound by these ranges, afteradministration of the dosage form.

In some embodiments, the dosage form may also be administered to relieveneuropathic pain, including diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies,phantom limb pain, sciatica, pudendal neuralgia, and central pain. Othercauses of neuropathic pain may include, but are not limited to,cancer-related pain, lumbar nerve root compression, spinal cord injury,post-stroke pain, central multiple sclerosis pain, HIV-associatedneuropathy, and radio-therapy or chemo-therapy associated neuropathy.The neuropathic pain treated may be chronic or acute.

In some methods, the dosage form may be administered to relieveinflammatory pain including inflammatory musculoskeletal pain, pain dueto injury, arthritis pain, and complex regional pain syndrome. In otherembodiments, the inflammatory pain may be chronic or acute.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include but are not limited topain associated with osteoarthritis, erosive osteoarthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, sero-negative (non-rheumatoid)arthropathies, non-articular rheumatism, peri-articular disorders,neuropathic arthropathies including Charcot's foot, axialspondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.The inflammatory joint disease treated may be chronic or acute.

For some methods, the meloxicam may be administered to relievemusculoskeletal pain. Examples of musculoskeletal pain may include, butare not limited to, back pain, low back pain (e.g., lumbosacral pain),neck pain, infection, cramps, tendonitis, epidondylitis, carpal tunnelsyndrome, joint pain, fibromyalgia, pain due to injury, Tunnelsyndromes, pain associated with bone fractures, sprains, fibrousdysplasia, osteogenesis imperfecta, Paget's disease of bone, transientosteoporosis, and transient osteoporosis of the hip. In otherembodiments, the musculoskeletal pain may be chronic or acute.

A human being that is treated for a disease or condition with the dosageforms described herein may be of any age. For example the person mayhave an age of about 10 years to about 90 years, about 20 years to about80 years, about 30 years to about 75 years, about 40 years to about 70years, about 1 year to about 16 years, about 80 years to about 95 years,about 18 years or more, about 20 years or more, about 25 years or more,about 30 years or more, about 40 years or more, about 45 years or more,about 50 years or more, about 55 years or more, about 60 years or more,about 65 years or more, or any other age in a range bounded by, orbetween, these values.

In some embodiments, a human being that is treated for a disease orcondition with a dosage form comprising meloxicam or another NSAID hassuffered from the pain or condition associated with the pain for atleast 1 day, at least one week, at least 2 weeks, at least 1 month, atleast 6 weeks, at least 2 months, at least 3 months, at least 6 months,or at least 1 year, or any duration in a range bounded by, or between,these values.

A cyclodextrin used in a dosage form with meloxicam could include acyclodextrin, a cyclodextrin derivative, and/or a salt thereof. Aninclusion complex of meloxicam and cyclodextrin may be morewater-soluble relative to the non-complexed meloxicam. The cyclodextrinmay be a naturally-occurring cyclodextrin (e.g., α, β, orγ-cyclodextrins) or a synthetic cyclodextrin. In some embodiments,α-cyclodextrins, derivatives, or salts thereof may be used.α-Cyclodextrins may include, but are not limited to,(2,3,6-tri-O-acetyl)-α-cyclodextrin,(2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin,6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin,(6-O-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin,succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, orcombinations thereof.

In some embodiments, β-cyclodextrins, derivatives, or salts thereof maybe used. β-cyclodextrins may include, but are not limited to,hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin,glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin,6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin,6-azido-6-deoxy-β-cyclodextrin,(2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin,dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD),(2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin,(2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin,(2,3,6-tri-O-methyl)-β-cyclodextrin,(2,3,6-tri-O-acetyl)-β-cyclodextrin,-(2,3,6-tri-O-benzoyl)-β-cyclodextrin,(2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin,6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin,diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin,(3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin,(6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin,(6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin,succinyl-(2-hydroxypropyl)-β-cyclodextrin,(2,6-di-O-)ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin(CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD),(2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin(HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD),(2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin,methyl-β-cyclodextrin,silyl((6-O-tert-butyldimethyl)-2,3,-di-0-acetyl)-β-cyclodextrin,succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomlymethylated-β-cyclodextrin, branched-β-cyclodextrin, or combinationsthereof.

In other embodiments, a β-cyclodextrin may be a sulfoalkyl ethercyclodextrin, derivative, or salt thereof. Examples of sulfoalkyl ethercyclodextrin derivatives may include, but are not limited to, sulfobutylether-β-cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In someembodiments, a SBEβCD may have about 4-8, about 5-8, about 4-7, about6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

In some embodiments, γ-cyclodextrins, derivatives, or salts thereof maybe used. γ-cyclodextrins may include carboxymethyl-γ-cyclodextrin,(2,3,6-tri-O-acetyl)-γ-cyclodextrin,(2,3,6-tri-O-methyl)-γ-cyclodextrin, (2,6-di-O-pentyl)-γ-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-γ-cyclodextrin,6-bromo-6-deoxy-γ-cyclodextrin, 6-iodo-6-deoxy-γ-cyclodextrin,(6-O-t-butyldimethylsilyl)-γ-cyclodextrin, succinyl-γ-cyclodextrin,hydroxypropyl-γ-cyclodextrin (2-hydroxypropyl)-γ-cyclodextrin,acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or combinations thereof.

In some embodiments, the dosage form may include a bicarbonate, such assodium bicarbonate, potassium bicarbonate, magnesium bicarbonate,calcium bicarbonate, ammonium bicarbonate, or a combination thereof. Abicarbonate may help to increase bioavailability of the meloxicam.

In other embodiments, the dosage form may include a carbonate,derivatives, or salts thereof. Examples of carbonates may includealuminum carbonate, ammonium carbonate, barium carbonate, calciumcarbonate, cobalt(II) carbonate, lanthanum carbonate, lithium carbonate,magnesium carbonate, manganese(II) carbonate, potassium carbonate,sodium carbonate, or combinations thereof.

In some embodiments, enhanced bioavailability of the dosage form may beachieved in treating one of these conditions by administering a dosageform comprising a salt form of the meloxicam, by creating an inclusioncomplex with meloxicam and cyclodextrin, and/or by including abicarbonate. This may allow a reduced molar amount of the meloxicam tobe used as compared to other meloxicam dosage forms.

Unless otherwise indicated, any reference to a compound herein, such asmeloxicam or a cyclodextrin, by structure, name, or any other means,includes pharmaceutically acceptable salts, alternate solid forms, suchas polymorphs, solvates, hydrates, enantiomers, tautomers,deuterium-modified forms, or any other chemical species that may rapidlyconvert to a compound described herein under conditions in which thecompounds are used as described herein.

In some embodiments, use of a cyclodextrin, a carbonate, or abicarbonate may improve the oral bioavailability of meloxicam by atleast about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70%, atleast about 80%, at least about 90%, up to about 100%, up to about 200%,or any amount in a range bounded by, or between, these values ascompared to administration of meloxicam alone.

Due to the improved bioavailability, the dosage form may contain, or asubject may receive, on a molar basis, less of the meloxicam than wouldotherwise be administered. For example, a dosage form may contain, or amammal may receive, at least about 10 mole % less, at least about 20mole % less, at least about 30 mole % less, at least about 40 mole %less, at least about 50 mole % less, at least about 60 mole % less, atleast about 70 mole % less, at least about 80 mole % less, at leastabout 85 mole % less, and/or up to about 90 mole % less, 95 mole % less,or any amount in a range bounded by, or between, these values as wouldotherwise be administered of meloxicam.

In other embodiments, use of other NSAIDs, opioids, or other painmedications may be reduced by at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, or at least about 90%, up to about 100%, as compared to the use ofother NSAIDs, opioids or other pain medications without administrationof meloxicam with cyclodextrin, carbonate, and/or bicarbonate.

In some embodiments, a dosage form may contain meloxicam in an amountfrom about 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about1-35 mg; about 1-25 mg; about 1-15 mg; about 5-20 mg; about 5-10 mg;about 5-15 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; about40-50 mg; about 5 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30mg; or any amount in a range bounded by, or between, any of thesevalues. These doses may be a safe dose for repeated administration, suchas once hourly dosing to once daily dosing, twice daily dosing, dosingone to 12 times daily, doing 3, 4, 5, or 6 times daily, etc. In someembodiments, the meloxicam may be safely administered 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times aday, once a day, or less frequently, such as once a week, once every twoweeks, once a month, etc.

For some dosage forms, meloxicam forms a complex with thesubstituted-α-cyclodextrin or other another cyclodextrin which may beformulated into a solid dosage form. Such a dosage form may be suitablefor oral administration. A meloxicam-cyclodextrin inclusion complex mayalso be dissolved in water or another solvent to form a parenteralformulation. However, physical mixtures of meloxicam and thesubstituted-β-cyclodextrin or other cyclodextrins may also be used inoral or parenteral dosage forms.

Formation of an inclusion complex of meloxicam and a cyclodextrin mayhelp to improve the properties of a dosage form. For some inclusioncomplexes, the meloxicam and the cyclodextrin (e.g., SBEβCD) may have amolar ratio of about 0.5-2 (a molar ratio of 0.5 is 0.5 moles ofmeloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8,about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3,about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or anyratio in a range bounded by any of these values.

For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed ina weight ratio to the meloxicam within the range from about 1-1000 (e.g.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1); about1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6, about5-7, about 6-8, about 7-9, about 8-10, or any weight ratio in a rangebounded by, or between, any of these values. For some dosage forms, acyclodextrin (e.g., SBEβCD) may be employed in a weight ratio to themeloxicam within the range from about 0.001-1 (e.g. 0.1 g ofcyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); about0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weightratio in a range bounded by, or between, any of these values. Each typeof cyclodextrin employed may have a different ratio.

For some dosage forms, the cyclodextrin may be present in an amount fromabout 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about60-100 mg; about 80-100 mg; about 80-120 mg; about 100-120 mg; about100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90 mg; about40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amountin a range bounded by, or between, any of these values.

For some methods, the inclusion complex of meloxicam and cyclodextrinsuch as a substituted-β-cyclodextrin is delivered orally (for example bytablet, capsule, elixir, or the like). Other potential routes ofadministration include intravenous, intramuscular, intranasal,lyophilized parenteral, subcutaneous, transdermal, transmucosal, orthrough other parenteral means. The meloxicam may also be deliveredalone or non-complexed with cyclodextrin.

Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) inamount from about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about200-800 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530 mg; about440-540 mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about480-580 mg; about 490-590 mg; about 500-600 mg; about 600-700 mg; about700-800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or anyamount in a range bounded by, or between, any of these values.

Some dosage forms contain a carbonate in amount from about 1-1000 mg;about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about500-1000 mg; about 100-500 mg; about 100-300 mg; about 200-800 mg; about500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about400-500 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about800-900 mg; about 150-650 mg; about 350-850 mg; or any amount in a rangebounded by, or between, any of these values.

In some embodiments, the daily dose of meloxicam (e.g., an oral dose, aparenteral dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg,about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg,about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg,about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about20-25 mg, about 25-30 mg, about 30-35 mg, or any amount in a rangebounded by any of these values.

In some embodiments, the weekly dose of meloxicam (e.g., an oral dose)is about 1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg;about 10-100 mg; about 10-150 mg; about 10-300 mg; about 20-150 mg;about 20-60 mg; about 30-70 mg; about 40-60 mg; about 50-70 mg; about70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about 100-150 mg;about 30-100 mg; or any amount in a range bounded by, or between, any ofthese values. The weekly dose may be given as a single dose, given onceduring the week, or may be given in 2, 3, 4, 5, 6, or 7 individual dosesduring the week.

In some embodiments, the monthly dose of meloxicam (e.g., an oral dose),or a dose administered over a period of a month, is about 5000 mg orless; about 4000 mg or less; about 3000 mg or less; about 2000 mg orless; about 1000 mg or less; about 700 mg or less; about 600 mg or less;about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg;about 10-600 mg; about 40-600 mg; about 50-600 mg; about 40-400 mg;about 50-200 mg; about 200-240 mg; about 240-280 mg; about 280-320 mg;about 320-360 mg; about 360-400 mg; about 400-450 mg; about 450-500 mg;about 500-600 mg; about 250-350 mg; about 100-600 mg; about 40-2000 mg;about 40-800 mg; about 100-900 mg; about 100-800 mg; about 40-1000 mg;about 50-1000 mg; about 100-1000 mg; or any monthly dose in a rangebounded by, or between, any of these values. A monthly dose may be givenas a single dose, or as two or more individual doses administered duringthe month. In some embodiments, the monthly dose is administered in 2 or3 bi-weekly doses. In some embodiments, the monthly dose is administeredin 4 or 5 weekly doses. In some embodiments, the monthly dose isadministered in 28 to 31 daily doses, or in 56 to 62 daily doses ormore. In some embodiments, the monthly dose is administered in 5 to 15individual doses during the month. The monthly dose may be administeredfor only 1 month, or may be repeatedly administered for 2 or moremonths.

In other embodiments, the dosage form may be administered weekly forabout one, two, three, four, or more consecutive weeks, every other weekor bi-weekly, or once every three weeks. This regimen may be repeatedonce weekly, twice in a month, three times in a month, once monthly,once every two months, once every three months, or as directed by amedical professional.

In certain embodiments, the pharmaceutical composition results inincreased bioavailability (e.g., reduced T_(max), increased C_(max),increased AUC, etc.) of the meloxicam from the dosage form as comparedto a dosage form containing meloxicam but not containing a cyclodextrin,an acid inhibitor, or a buffering agent (such as a bicarbonate). In someembodiments, the bioavailability of meloxicam will increase withmultiple dosing. For example, the bioavailability of meloxicam in thedosage form may increase after about 1-10 days of dosing; about 2-6 daysof dosing; about 3-5 days of dosing; about 4-6 days of dosing; about 5-8days of dosing; about 5 days of dosing; about 6 days of dosing; about 7days of dosing; about 8 days of dosing; about 10 days of dosing; about15 days of dosing; or time in any range bounded by, or between, any ofthese values; as compared to the bioavailability of meloxicam in adosage form not containing a cyclodextrin, an acid inhibitor, or abuffering agent (such as a bicarbonate).

Some of the dosage forms may result in a desired range for an area underthe plasma concentration curve (AUC) of meloxicam. For example thedosage with meloxicam may result in an AUC of meloxicam of about 1-150μg·hr/mL; about 10-30 μg·hr/mL; about 20-40 μg·hr/mL; about 30-50μg·hr/mL; about 40-60 μg·hr/mL; about 50-70 μg·hr/mL; about 60-80μg·hr/mL; about 70-90 μg·hr/mL; about 80-100 μg·hr/mL; about 10-100μg·hr/mL; about 50-150 μg·hr/mL; about 25-125 μg·hr/mL; about 75-150μg·hr/mL; about 20-50 μg·hr/mL; about 40-70 μg·hr/mL; about 60-90μg·hr/mL; about 80-110 μg·hr/mL; about 100-130 μg·hr/mL; about 120-150μg·hr/mL; or any AUC in a range bounded by, or between, any of thesevalues.

Unless otherwise indicated, the AUC refers to the AUC calculated to thelast measured concentration (AUC_(0-t)), over a period of 24 hours(AUC₀₋₂₄), or extrapolated to infinity (AUC_(0-inf)).

For some acute pain conditions, such as migraine and other types ofheadache, the AUC for a short period after oral administration, such asan AUC measured over 6 hours (or AUC₀₋₆), may be of particular interest.For example, some dosage forms may result in an AUC₀₋₆ of at least about6 μg·hr/mL; at least about 7 μg·hr/mL; at least about 8 μg·hr/mL; atleast about 9 μg·hr/mL; about 6-10 μg·hr/mL; about 7-11 μg·hr/mL; about8-12 μg·hr/mL; about 9-13 μg·hr/mL; or any AUC in a range bounded by, orbetween, any of these values.

In some embodiments, the dosage form may result in a C_(max) ofmeloxicam of about 10-2500 ng/mL; about 100-2250 ng/mL; about 500-2000ng/mL; about 1000-2500 ng/mL; about 1000-2000 ng/mL; about 100-900ng/mL; about 750-1500 ng/mL; about 1250-2000 ng/mL; about 1500-2300ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL; about 50-500 ng/mL;about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200 ng/mL; about1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100 ng/mL; about1500-1900 ng/mL; about 1600-2100 ng/mL; about 1700-2000 ng/mL; about1800-2000 ng/mL; about 1900-2500 ng/mL; about 150-1700 ng/mL; about1600-1800 ng/mL; about 1700-1900 ng/mL; about 1800-2000 ng/mL; about1900-2100 ng/mL; about 2000-2200 ng/mL; about 2100-2300 ng/mL; about2200-2400 ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; or anyC_(max) in a range bounded by, or between, any of these values.

For example, a method described herein may reduce the T_(max) ofmeloxicam. In some embodiments, the method may include treating apatient to achieve the T_(max) of meloxicam in the patient within about10 minutes; about 20 minutes; about 30 minutes; about 40 minutes; about50 minutes; about 60 minutes; about 70 minutes; about 80 minutes; about90 minutes; about 100 minutes; about 110 minutes; about 120 minutes;about 180 minutes; about 1-10 hr; about 2-9 hr; about 3-7 hr; about 4-6hr; about 1-5 hr; about 2-7 hr; about 3-8 hr; about 4-9 hr; about 1-4hr; about 2-5 hr; about 3-6 hr; about 4-7 hr; about 5-8 hr; about 6-9hr; about 7-10 hr; after administration or any T_(max) in a rangebounded by, or between, any of these values.

In some embodiments, an oral dosage form may have a T_(max) of meloxicamthat is shorter than would be achieved by administering meloxicam byintramuscular injection. In some embodiments, an oral dosage form mayhave a T_(max) of meloxicam that is shorter, or may increase meloxicamplasma levels at a faster rate, by a factor of at least about 1.5, about2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about10, about 12, about 15, about 20, or by a factor of about 1.5-1000,about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about7-100, about 8-100, about 9-100, about 10-100, about 12-100, about15-100, about 20-100, or by a factor in a range bounded by any of thesevalues.

In some embodiments, a dosage form comprising meloxicam may result in aplasma concentration of meloxicam at 12 hours that is about 0.01-0.5μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about 0.7-0.9 μg/mL;about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL;about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about 2.1-2.3μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL;about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about 3.1-3.3μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL;about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about 3.7-3.9 μg/mL; about3.8-4 μg/mL; or any plasma concentration in a range bounded by, orbetween, any of these values.

In some embodiments, meloxicam is administered at a dose that results ina meloxicam plasma level (such as a Ca, or average plasma level) ofabout 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL;about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL;about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL;about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 0.1-20 μg/mL; about 0.5-15μg/mL; about 0.5-10 μg/mL; about 5-15 μg/mL; about 10-20 μg/mL; about7.5-15 μg/mL; about 2-10 μg/mL; about 1-8 μg/mL; about 1-6 μg/mL; about1-2 μg/mL; about 0.5-3.5 μg/mL; about 0.5-7 μg/mL; about 12-20 μg/mL;about 8-12 μg/mL; about 1-4 μg/mL; about 4-7 μg/mL; about 7-11 μg/mL;about 11-15 μg/mL; about 15-19 μg/mL; about 16-20 μg/mL; or any amountof meloxicam plasma level in a range bounded by, or between, any ofthese values.

One embodiment is a method for reducing the risk of gastrointestinalside effects in people taking NSAIDs for pain relief and for otherconditions, particularly during chronic treatment, and improving thebioavailability of the NSAID. In one embodiment, the method involves theadministration of a product that combines: a) an agent that activelyraises intragastric pH; and b) an NSAID that is formulated with acyclodextrin. In another embodiment, the method involves theadministration of a product that combines: a) an agent that activelyraises intragastric pH; b) an NSAID that is formulated with acyclodextrin; and c) a buffering agent. Either short or long acting acidinhibitors can be effectively used in the dosage forms. This method hasthe added benefit of being able to protect patients from othergastrointestinal ulcerogens whose effect may otherwise be enhanced bythe disruption of gastroprotective prostaglandins due to NSAID therapy.

The meloxicam formulation in an aqueous parenteral form may include abuffer to adjust the pH of an aqueous formulation, within a range ofabout 2 to about 5; about 3.5 to about 5; about 5 to about 11; about 6to about 9; about 6 to about 8; about 6 to about 7; or any other pH in arange bounded by, or between, any of these values. The meloxicamformulation in an oral form may include a buffer to adjust the pH ofstomach fluid within a range of about 2 to about 5; about 3.5 to about5; about 5 to about 11; about 6 to about 9; about 6 to about 8; about 6to about 7; or any other pH in a range bounded by, or between, any ofthese values. Examples of buffers suitable for use herein includesulfate buffers, phosphate buffers, borate buffers, carbonate buffers,citrate buffers, etc.

In some embodiments, the dosage form may be formulated for oraladministration, for example, with an inert diluent or with an ediblecarrier, or it may be enclosed in hard or soft shell gelatin capsules,compressed into tablets, or incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with an excipient and used in the form of ingestibletablets, buccal tablets, coated tablets, troches, capsules, elixirs,dispersions, suspensions, solutions, syrups, wafers, patches, and thelike.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the unit dosageform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non-toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

The dosage form may further comprise a second therapeutically activeagent, such as an acid inhibitor or an analgesic.

In some embodiments, the dosage form may further comprise an acidinhibitor present in an amount effective to raise the gastric pH of apatient to at least 2, to at least 2.5, to at least 3, to at least 3.5,to at least 4, and more to at least 5, when one or more unit dosageforms are administered. The term “acid inhibitor” refers to agents thatinhibit gastric acid secretion and increase gastric pH. Specific H₂blockers, also referred to as H₂ antagonists or histamine H₂ blockers orantagonists, that may be used include but are not limited to cimetidine,ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine,or combinations thereof.

Other agents that may be effectively used as acid inhibitors are theproton pump inhibitors such as omeprazole, esomeprazole, pantoprazole,lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazoleand tenatoprazole. In some embodiments the daily dose of the acidinhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg, about 20 mg,about 30 mg, about 40 mg or any other amount in a range bounded by, orbetween, any of these values.

Examples of particular proton pump inhibitors include esomeprazole,present in unit dosage forms in an amount of between 5 mg and 50 mg;omeprazole, present in unit dosage forms in an amount of between 5 mgand 50 mg; lansoprazole, present in unit dosage forms in an amount ofbetween 5 mg and 150 mg (and preferably at between 5 mg and 30 mg); andpantoprazole, present in unit dosage forms in an amount of between 10 mgand 200 mg. In some embodiments, the proton pump inhibitor is present inthe dosage form in an amount of about 10-30 mg, about 20-40 mg, about30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90mg, or about 80-100 mg. Recently, a newer class of acid inhibitor hasbeen developed which competes with potassium at the acid pump. Thecompounds in this class have been referred to as “reversible proton pumpinhibitors” or “acid pump antagonists” and may also be used. Examplesinclude AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan andsoraprazan (see WO9605177 and WO9605199). Other compounds in this groupare H-335/25 (AstraZeneca, Dialog file 128, accession number 020806);Sch-28080 (Schering Plough, Dialog file 128, accession number 009663);Sch-32651 (Schering Plough, Dialog file 128, accession number 006883)and SK&F-96067 (CAS Registry no. 115607-61-9).

The second therapeutically active agent may include an analgesic such asa second non-steroidal anti-inflammatory drug, an opioid, a steroid, atriptan, etc. In some embodiments, the dosage form or treatment alsofurther comprises administering a second non-steroidal anti-inflammatorydrug in an amount effective to reduce or eliminate pain or inflammation.The NSAID may include, but is not limited to, celecoxib, rofecoxib,lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522,L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID forthe purposes of the present disclosure), ibuprofen, flurbiprofen,ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac,lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone,diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac,tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamicacid, oxyphenbutazone, azapropazone, phenylbutazone, or combinationsthereof. It will be understood that, for the purposes of the presentdisclosure, reference to an acid inhibitor, NSAID, or analgesic agentwill include all of the common forms of these compounds and, inparticular, their pharmaceutically acceptable salts. The amounts ofNSAIDs which are therapeutically effective may be lower in the currentembodiments than otherwise found in practice due to potential positivekinetic interaction and NSAID absorption in the presence of an acidinhibitor, and or in the presence of a buffering agent.

In other embodiments, the dosage form or treatment may further compriseadministering an opioid in an amount effective to reduce or eliminatepain or inflammation. The opioid may include, but is not limited to,(dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprodine,bezitramide, buprenorphine, butorphanol, carfentanyl, desmethylprodine,dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone,dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine,fentanyl, ketobemidone, lefetamine, levacetylmethadol, levomethorphan,levorphanol, loperamide, meperidine, meptazinol, methadone,methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone,nicomorphine, ohmefentanyl, oripavine, oxycodone, oxymorphone, PEPAP,paramorphine, pentazocine, phenazocine, piritramide, prodine,remifentanil, sufentanil, tapentadol, tilidine, tramadol, orcombinations thereof.

Useful triptans may include sumatriptan, rizatriptan, naratriptan,eletriptan, donitriptan, almotriptan, frovatriptan, alvitriptan,zolmatriptan, etc. In some embodiments, the triptan comprisesrizatriptan. In some embodiments, the dosage form may contain about 1-5mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about15-20 mg, or about 20-30 mg, of the triptan, such as rizatriptan, or anyamount in a range bounded by any of these values.

A pharmaceutical composition may be in the form of a tablet or capsulethat has: (a) the acid inhibitor; and/or (b) a buffering agent; and (c)the non-steroidal anti-inflammatory drug (NSAID) present in an amounteffective to reduce or eliminate pain or inflammation in a patient uponadministration of one or more of said unit dosage forms. The componentsof the pharmaceutical composition may be in an immediate or extendedrelease form individually or in total.

The term “unit dosage form” as used herein refers to a single entity fordrug administration. For example, a single tablet or capsule combiningboth an acid inhibitor and an NSAID would be a unit dosage form. A “unitdosage form” (or “unit dose form”) may also be referred to as a “fixeddosage form” (or “fixed dose form”) or “fixed dosage combination” (or“fixed dose combination”) and are otherwise interchangeable. In oneembodiment, the unit dosage form is a multilayer tablet.

In another embodiment, the unit dosage form is suitable for oraladministration to a patient. In yet another embodiment, the unit dosageform is a tablet. In still another embodiment, the unit dosage form is amultilayer tablet comprising a single core and one or more layersoutside of the core.

Some dosage forms may comprise a first layer comprising meloxicam, anSBEβCD, and a bicarbonate; and a second layer comprising a secondtherapeutically active agent and a bicarbonate.

The first layer may contain, for example, any amount of meloxicam in oneof the ranges recited above. For example, all of the meloxicam in thedosage form may be present in the first layer. The second layer maycontain all of the second therapeutically active agent, such that anyamount in the ranges recited above with respect to the secondtherapeutically active agent may apply to the second layer.

In some embodiments, the first layer contains about 10-200 mg, about50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about100 mg of the bicarbonate, such as sodium bicarbonate, or any amount ofthe bicarbonate in a range bounded by any of these values.

In some embodiments, the second layer contains about 100-500 mg, about200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, orabout 400 mg of the bicarbonate, such as sodium bicarbonate, or anyamount of the bicarbonate in a range bounded by any of these values.

In some embodiments, the pharmaceutical composition may have aneffective amount of meloxicam, a cyclodextrin, and a carbonate orbicarbonate to increase bioavailability of meloxicam. In otherembodiments, the pharmaceutical composition may have an effective amountof meloxicam, sulfobutylether-β-cyclodextrin (SBEβCD), and sodiumbicarbonate to increase bioavailability of meloxicam or reduce theT_(max) of meloxicam.

Some oral dosage forms may have enteric coatings or film coatings. Insome embodiments, a dosage form may comprise a tablet or a capsulehaving an enteric coating. In some embodiments, a dosage form maycomprise a tablet or a capsule having a film coating.

An embodiment of the present disclosure is directed to a pharmaceuticalcomposition in unit dosage form suitable for administration to apatient, comprising:

(a) esomeprazole, which may or may not be surrounded by an entericcoating;

(b) sodium or potassium bicarbonate and/or sodium or potassiumcarbonate; and

(c) meloxicam, which may or may not be formulated with a cyclodextrin,and which may or may not be surrounded by an enteric coating

In certain embodiments, the pharmaceutical composition results in fasterrelease or dissolution of the meloxicam from the dosage form as comparedto a dosage form containing meloxicam but not containing the acidinhibitor, or not containing the buffering agent.

The following embodiments are contemplated:

Embodiment 1

An inclusion complex of meloxicam in a cyclodextrin.

Embodiment 2

A dosage form comprising: 1) the inclusion complex of embodiment 1, or2) meloxicam and a carbonate or a bicarbonate.

Embodiment 3

The dosage form of embodiment 2 comprising the inclusion complex,wherein the cyclodextrin comprises substituted β-cyclodextrin.

Embodiment 4

The dosage form of embodiment 3, wherein the substituted β-cyclodextrinis a sulfobutyl ether R-cyclodextrin (SBEβCD) or hydroxypropylβ-cyclodextrin (HPBCD).

Embodiment 5

The dosage form of embodiment 4, wherein the cyclodextrin is the SBEβCD.

Embodiment 6

The dosage form of embodiment 5, wherein the SBEβCD has about 6 to about7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

Embodiment 7

The dosage form of embodiment 6, wherein the meloxicam and the SBEβCDhave a molar ratio of about 0.8 to about 1.2.

Embodiment 8

The dosage form of embodiment 6, wherein the meloxicam and the SBEβCDhave a molar ratio of about 1.

Embodiment 9

The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8, comprising abicarbonate.

Embodiment 10

The dosage form of embodiment 9, wherein the bicarbonate comprisessodium bicarbonate.

Embodiment 11

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is anoral dosage form.

Embodiment 12

The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein about50 mg to about 200 mg of SBEβCD is present in the dosage form.

Embodiment 13

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,wherein the carbonate or bicarbonate is present in an amount in a rangeof about 400 mg to about 600 mg.

Embodiment 14

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13,wherein the T_(max) of meloxicam is decreased as compared to a dosageform not having a carbonate, a bicarbonate, or a cyclodextrin.

Embodiment 15

The method of embodiment 14, wherein the T_(max) of meloxicam isachieved in the patient at a time in a range of about 10 minutes toabout 180 minutes after administration.

Embodiment 16

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, or 15, having an oral bioavailability of meloxicam that is higherthan a dosage form not having a carbonate, a bicarbonate, or acyclodextrin.

Embodiment 17

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20, further comprising an acid inhibitor.

Embodiment 18

The dosage form of embodiment 17, wherein the acid inhibitor is a protonpump inhibitor.

Embodiment 19

The dosage form of embodiment 18, wherein the proton pump inhibitor isesomeprazole.

Embodiment 20

The dosage form of embodiment 19, wherein about 30 mg to about 50 mg ofesomeprazole is present in the dosage form.

Embodiment 21

A method of administering meloxicam orally, comprising orallyadministering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a patient in need oftreatment.

Embodiment 22

The method of embodiment 21, wherein the dosage form is administered totreat pain.

Embodiment 23

The method of embodiment 21, wherein the dosage form is administered totreat inflammatory pain.

Embodiment 24

The method of embodiment 21, wherein the dosage form is administered totreat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoidarthritis.

Embodiment 25

A method of administering meloxicam intravenously, comprisingintravenously administering a dosage form of embodiment 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 13, 14, or 15, to a patient in need of treatment.

Example 1

The effect of varying amounts of potassium carbonate (K₂CO₃) and sodiumbicarbonate (NaHCO₃) on the pH of acidic media was tested. The acidicmedia was chosen to simulate gastric conditions. K₂CO₃ or NaHCO₃ wasadded to 50 mL of a 0.01 N HCl solution (pH 2). The pH of the solutionwas measured after addition of the K₂CO₃ or NaHCO3. Deionized water (240mL) was then added to the mixture and pH was measured again. The resultsare shown in Tables 1-4.

TABLE 1 Results with K₂CO₃ (0.01N HCl) K₂CO₃ (mg) pH 25 2.84 35 6.29 458.05 50 8.29 100 9.43 200 10.14 300 10.39 400 10.55 450 10.58

TABLE 2 Results with K₂CO₃ (0.01N HCl + Water) K₂CO₃ (mg) pH 200 10.27300 10.46 400 10.57 450 10.63

TABLE 3 Results with NaHCO₃ (0.01N HCl) NaHCO₃ (mg) pH 200 5.28 300 5.90400 6.44 450 6.86 500 8.23 750 8.30 1000 8.36

TABLE 4 Results with NaHCO₃ (0.01N HCl + Water) NaHCO₃ (mg) pH 200 5.41300 5.89 400 6.11 450 6.46 500 8.33 750 8.54 1000 8.60

Example 2

Tablets containing meloxicam and combinations of cyclodextrin, K₂CO3, orNaHCO₃ were manufactured and tested for dissolution. Tablets containingmeloxicam alone (MOBIC®) were purchased and also tested for dissolution.The tested tablets are listed in Table 5. Meloxicam in the form ofmeloxicam/cyclodextrin inclusion complexes was used in the tabletscontaining meloxicam and cyclodextrin. The inclusion complexes wereformed by mixing meloxicam and cyclodextrin in an aqueous pH-adjustedsolution. The pH of the solution was adjusted using buffering agents.The resulting soluble meloxicam/cyclodextrin inclusion complexes werethen spray dried. This spray-dried dispersion was used in themanufacture of the tablets containing cyclodextrin.

TABLE 5 Tablets Tablet A 15 mg meloxicam + 25 mg K₂CO3 Tablet B 15 mgmeloxicam + 50 mg K₂CO3 Tablet C 15 mg meloxicam + 100 mg K₂CO3 Tablet D15 mg meloxicam + 150 mg K₂CO3 Tablet E 15 mg meloxicam + 500 mg NaHCO3Tablet F 15 mg meloxicam + 100 mg SBEβCD Tablet G 15 mg meloxicam + 100mg SBEβCD + 25 mg K₂CO3 Tablet H 15 mg meloxicam + 100 mg SBEβCD + 50 mgK₂CO3 Tablet I 15 mg meloxicam + 100 mg SBEβCD + 100 mg K₂CO3 Tablet J15 mg meloxicam + 100 mg SBEβCD + 150 mg K₂CO3 Tablet K 15 mgmeloxicam + 100 mg SBEβCD + 500 mg NaHCO3 Tablet L 15 mg meloxicam(MOBIC ®)

Dissolution testing in acidic medium (chosen to simulate gastricconditions) was performed by placing the tablets in a 0.01 N HClsolution, at an agitation rate of 75 RPM, and vessel temperature ofapproximately 37° C. The results are presented in Tables 6 and in FIGS.1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120minutes) are presented as percent (%) of meloxicam dissolved.

TABLE 6 Dissolution Results 30 120 0 mins 15 mins mins 45 mins 60 mins90 mins mins Tablet A 0% 23% 17% 15% 13% 12% 11% Tablet B 0% 27% 20% 17%16% 17% 15% Tablet C 0% 31% 26% 25% 24% 23% 21% Tablet D 0% 30% 26% 25%24% 23% 22% Tablet E 0% 50% 66% 77% 84% 92% 95% Tablet F 0% 26% 17% 14%12% 11% 10% Tablet G 0% 48% 39% 26% 20% 16% 14% Tablet H 0% 44% 30% 22%17% 16% 13% Tablet I 0% 32% 33% 27% 21% 16% 15% Tablet J 0% 26% 27% 19%15% 12% 11% Tablet K 0% 85% 86% 86% 86% 86% 86% Tablet L 0% 2% 2% 2% 2%2% 2%

Dissolution of meloxicam was greater with the tablets containing variouscombinations of meloxicam and cyclodextrin, K₂CO₃, or NaHCO₃, ascompared to tablets containing meloxicam alone. For example, after 120minutes, dissolution of meloxicam tablets containing NaHCO₃ was 95% ascompared to 2% for tablets containing meloxicam alone.

Dissolution of meloxicam increasing with increasing amounts of K₂CO₃ inthe absence of cyclodextrin. However, in the presence of cyclodextrin,increasing amounts of K₂CO₃ did not appear to increase meloxicamdissolution. At the highest dose of potassium bicarbonate tested,meloxicam dissolution in the presence of cyclodextrin was reduced byapproximately 50% as compared to meloxicam dissolution in the absence ofcyclodextrin at 120 minutes.

Dissolution of meloxicam with NaHCO₃ was significantly greater than thatobserved with the highest dose of K₂CO₃ at 15 minutes (50% versus 30%),and at 120 minutes (92% versus 23%). Meloxicam dissolution in thepresence of cyclodextrin was also significantly greater with NaHCO₃ ascompared to the highest dose of K₂CO₃ at 15 minutes (85% versus 26%),and at 120 minutes (86% versus 12%). NaHCO₃ in the presence ofcyclodextrin increased meloxicam dissolution at 15 minutes as comparedto potassium bicarbonate which resulted in a reduction in dissolution.

Example 3

A bilayer tablet containing 1) an inclusion complex of SBEβCD withmeloxicam, and 2) sodium bicarbonate was prepared(SBEβCD-Meloxicam/Bicarbonate). The first layer contained an inclusioncomplex of 15 mg meloxicam and 100 mg SBEβCD, and 100 mg of sodiumbicarbonate. The second layer contained 40 mg of esomeprazole and 400 mgof sodium bicarbonate.

A total of 20 human subjects were randomly assigned in a 1:1 ratio totreatment with the SBEβCD-Meloxicam/Bicarbonate tablets described aboveor Mobic® tablets (15 mg meloxicam), once daily for 6 days under fastingconditions.

On the first day of dosing, plasma samples were collected forconcentration analysis of meloxicam at several time points.Concentrations of meloxicam were determined using LC-MS/MS.Pharmacokinetic parameters were calculated. The results are depicted inFIG. 11.

The median T_(max) for meloxicam, the trial's primary endpoint, was 9times faster for the SBEβCD-Meloxicam/Bicarbonate tablets as compared toMobic® (0.5 hour versus 4.5 hours respectively, p<0.0001).

The SBEβCD-Meloxicam/Bicarbonate tablets also demonstrated higher meanmaximum plasma concentration (C_(max)) (p=0.0018), faster time totherapeutic plasma concentration (p<0.0001), and faster time tohalf-maximal plasma concentration (p<0.0001) as compared to Mobic®.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodin all instances as indicating both the exact values as shown and asbeing modified by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

1. A method of improving dissolution of meloxicam in a stomach of amammal, comprising orally administering a solid dosage form comprisingboth a bicarbonate and meloxicam to the mammal, wherein the rate ofdissolution of meloxicam for the solid dosage form is improved ascompared with a reference dosage form that: 1) contains the same amountof meloxicam; 2) contains an amount of potassium carbonate that achievesabout the same pH as the bicarbonate; and 3) does not contain thebicarbonate.
 2. The method of claim 1, wherein the mammal is a humanbeing.
 3. The method of claim 1, wherein the solid dosage form furthercomprises a cyclodextrin.
 4. The method of claim 3, wherein thecyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD).
 5. Themethod of claim 1, wherein the solid dosage form further comprises anacid inhibitor.
 6. The method of claim 5, wherein the acid inhibitor isesomeprazole.
 7. The method of claim 1, wherein the solid dosage form isin a tablet form.
 8. The method of claim 1, wherein the solid dosageform comprises about 1 mg to about 50 mg of meloxicam.
 9. The method ofclaim 8, wherein the solid dosage form comprises about 15 mg ofmeloxicam.
 10. The method of claim 1, wherein the bicarbonate is sodiumbicarbonate or potassium bicarbonate.
 11. The method of claim 10,wherein the solid dosage form comprises about 100 mg to about 1000 mg ofsodium bicarbonate.
 12. The method of claim 11, wherein the solid dosageform comprises about 500 mg of sodium bicarbonate.
 13. The method ofclaim 6, wherein about 30 mg to about 50 mg of esomeprazole is presentin the solid dosage form.
 14. The method of claim 1, wherein, 120minutes after oral administration of the solid dosage form, thedissolution of meloxicam is at least about 3 times that of the referencedosage form.
 15. The method of claim 3, wherein, 120 minutes after oraladministration of the solid dosage form, the dissolution of meloxicam isat least about 5 times that of the reference dosage form.
 16. The methodof claim 1, wherein, 15 minutes after oral administration of the soliddosage form, the dissolution of meloxicam is at least 10% more than thatof the reference dosage form.
 17. The method of claim 3, wherein, 15minutes after oral administration of the solid dosage form, thedissolution of meloxicam is at least about 2 times that of the referencedosage form.
 18. The method of claim 1, wherein the solid dosage form isorally administered to the mammal to treat pain.
 19. The method of claim18, wherein the pain is inflammatory pain.
 20. The method of claim 1,wherein the solid dosage form is orally administered to the mammal totreat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoidarthritis.